Colon cancer is the third most common cancer and the third leading cause of cancer-related mortality in the United States. Approximately 10% of colorectal cancer develops within a small subset of serrated polyps, which is associated with the CpG Island Methylator Phenotype (CIMP). A number of genetic lesions have been associated with the serrated polyps, but the mechanisms that cause serrated adenomas and carcinomas to form are poorly understood. We have developed the first mouse model for serrated polyps. In HB28 mice, the combined expression of HB-EGF and an activated GPCR (US28) in the intestinal epithelium leads to development of lesions that share many morphological and biochemical similarities to the serrated polyps in humans. Strikingly, development of the serrated lesions appears to be dependent on both genetic and environmental factors. We hypothesize that the combined activity of HB-EGF and US28 induces disease development by up-regulating RAS/RAF signaling, which is seen in human serrated adenomas. We will directly test this hypothesis by comparing and contrasting HB28 mice with newly generated transgenic mice expressing activated Braf and Kras in the intestinal epithelium. Finally, we will determine if environmental factors such as microbes are required for development of serrated polyps. Together the studies outlined in this proposal should help define the molecular mechanisms accounting for development of serrated polyps.